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Transcriptional Regulation of Dormancy and Emergence in Breast Cancer

乳腺癌休眠和出现的转录调控

基本信息

批准号：
10658586
负责人：
PARTHA ROY
金额：
$ 40.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658586
关键词：
Actins Adopted Behavior Blood Vessels Brain Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Cancer Etiology Cells Cessation of life Clinical Collaborations Competence Cytoskeleton Data Dependence Developmental Biology Extracellular Matrix Extravasation Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Transcription Goals Grant Growth Human Impairment In Vitro Intervention Joints Life Link Liver Liver neoplasms Lung Lung Neoplasms Malignant Neoplasms Metastatic Neoplasm to the Bone Micrometastasis Modeling Neoplasm Metastasis Organ Organoids Osteoclasts Pathway interactions Patients Phenotype Publications Recording of previous events Regulation Research Personnel Role Sampling Serum Response Factor Site Stromal Cells Study models Testing Time Tissues Transcription Coactivator Transcriptional Regulation United States United States National Institutes of Health Up-Regulation Woman Zebrafish bone breast cancer progression breast cancer survival cancer cell cancer seeding conditioning connective tissue growth factor driving force improved in vivo intravital imaging lung colonization malignant breast neoplasm mortality mouse model myocardin neoplastic cell novel novel strategies pharmacologic prevent programs small molecule transcription factor tumor tumor microenvironment tumor progression

项目摘要

Breast cancer ranks second among cancer deaths in women in the United States. Breast cancer-related mortality primarily results from metastatic growth of disseminated cells. While dissemination of cancer cells occurs early during tumor progression, metastatic outgrowth of extravasated cancer cells often takes many years due to the dormant behavior of cancer cells. In principle, the survival of breast cancer patients should be improved if metastatic burden is reduced by either prolonging the dormancy of disseminated tumor cells or slowing down progressive metastatic growth. Our overarching goal is to identify tumor cell-intrinsic transcriptional programs that are critical for dormancy-to-emergence transition and progressive growth of established metastases in breast cancer. In the proposed study, we hypothesize that dormancy-to- emergence switch and progressive metastatic growth of breast cancer cells require the action of Myocardin- related transcription factor (MRTF), a transcriptional coactivator of serum-response factor (SRF). To test this hypothesis, we propose two specific aims. In Aim 1, we will conduct genetic and pharmacological proof-of- concept studies to establish the role of MRTF/SRF transcriptional axis in regulation of dormancy and metastatic growth of breast cancer cells. Aim 2 will test whether MRTF/SRF activity promotes metastatic growth of breast cancer cells through both tumor-intrinsic and –extrinsic mechanisms. The proposed studies will employ a highly comprehensive experimental strategy integrating inducible functional disruption and pharmacological intervention strategies, intravital imaging of tumor cell activity at metastatic sites, organotypic models of lung and liver tumor microenvironment to study tumor dormancy, mouse model studies, use of patient-derived organoids and clinical samples of BC, and multiplexed quantitative IHC. A successful completion of these studies will establish MRTF as a novel regulator of dormancy-emergence behavior of breast cancer cells with mechanistic details, and provide proof-of-concepts for pharmacological intervention of MRTF as a novel strategy to induce dormancy and curb metastatic growth in breast cancer.

乳腺癌在美国女性癌症死亡中排名第二。乳腺癌相关